CN107098908B - Preparation method and application of pyrrolopyrimidine compound - Google Patents
Preparation method and application of pyrrolopyrimidine compound Download PDFInfo
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- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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Abstract
The invention provides a preparation method and application of a pyrrolopyrimidine compound, and particularly provides a compound shown in formula I or a pharmaceutically acceptable salt thereof, a pharmaceutical composition containing the compound or the salt, a preparation method of the compound or the salt, and application of the compound or the salt as an immunosuppressant.
Description
Technical Field
The invention relates to a pyrrolopyrimidine compound or pharmaceutically acceptable salt thereof, a pharmaceutical composition containing the compound or salt, a preparation method thereof and application of the compound or salt as an immunosuppressant.
Background
JAK1 has a key role in a variety of cytokine and growth factor signaling pathways, and JAK1 dysregulation can lead to or contribute to disease or cause an inflammatory response. For example, in rheumatoid arthritis, interleukin 6 activation has a pro-inflammatory effect and antagonizing IL-6 directly or indirectly through JAK1 inhibition would provide clinical benefit.
Selective inhibitors of JAK1 have multiple therapeutic benefits over other JAK kinases for less selective inhibitors. For the selectivity of JAK2, a variety of important cytokines and growth factors signal through JAK2, including, for example, Erythropoietin (EPO) and Thrombopoietin (TPO). Such as reduced TPO signaling, will lead to megakaryocytopenia and possibly thrombocytopenia. Whereas, for JAK3 selectivity, JAK3 kinase deficient children may have severe combined immunodeficiency disease. The compounds of the invention are JAK inhibitors, and most of the compounds of the invention are JAK1 selective inhibitors. JAK1 selective inhibitors are compounds that preferentially inhibit JAK1 activity over other Janus kinases.
Therefore, there is an urgent need in the art to develop a compound having specific immunosuppressive activity.
Disclosure of Invention
The invention aims to provide a JAK1 enzyme selective inhibitor with a novel structure, and a preparation method and application thereof.
In a first aspect of the invention, there is provided a compound of formula I, or a pharmaceutically acceptable salt thereof,
wherein the content of the first and second substances,
R1selected from the group consisting of: H. substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C4-C10 heterocyclyl, substituted or unsubstituted C1-C10 heteroaryl, -RaC(O)Rb、-R1’-NRcC(O)Rband-R1’-N＝CRcRb(ii) a And said substitution refers to having one or more substituents selected from the group consisting of group a 1: substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C4-C10 heterocyclyl, substituted or unsubstituted C1-C10 heteroaryl, halogen, -NH2-OH and-CN;
each Ra、RbEach independently selected from the group consisting of: hydrogen, -CN, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C3-C8 alkynyl, substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C4-C10 heterocyclyl, and substituted or unsubstituted C1-C10 heteroaryl, and said substitution refers to having one or more substituents selected from the following group a 2: halogen, amino, nitro, -OH, -CN, C1-C4 alkyl, and C1-C4 haloalkyl;
Rcis H or C1-C3 alkyl;
R1' is phenyl or cyclohexyl;
wherein the C4-C10 heterocyclyl and C1-C10 heteroaryl each independently have 1-3 heteroatoms selected from N, O and S.
In another preferred embodiment, RbIs a substituted or unsubstituted C1-C8 alkyl group, a substituted or unsubstituted C2-C8 alkenyl group, or a substituted or unsubstituted C4-C10 heterocyclic group, and the substitution means having one or more substituents selected from the following group A4: halogen, -OH, -CN; the C4-C10 heterocyclyl has 1-3 heteroatoms selected from N, O and S.
In another preferred embodiment, the compound of formula I is selected from compounds of formula I-b or I-c as follows:
In another preferred embodiment, the compound of formula I is selected from the group consisting of:
N-methyl-N- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) phenyl-1, 4-diamine;
5-methyl-isoxazole- { 4-methyl- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) -amino ] -phenyl } -4-amide;
5-methyl-isoxazole- { 4-methyl- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) -amino ] -cyclohexyl } -amine;
2-cyano-3-hydroxy-2-butene- {4- [ methyl- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) -amino ] -phenyl ] -amide;
2-cyano-3-hydroxy-2-butene- {4- [ methyl- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) -amino ] -cyclohexyl ] -amide; and
3-hydroxy-2- (1- {4- [ methyl- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) -amino ] -iminophenyl } -ethyl) -2-butenenitrile.
In a second aspect of the invention, there is provided a process for the preparation of a compound of formula I-b, comprising the steps of:
reacting a compound of formula II with a compound of formula III in an inert solvent to provide a compound of formula I-b, wherein R1' is as defined above.
In another preferred embodiment, the inert solvent is selected from the group consisting of: dichloromethane, trichloromethane, 1, 2-dichloroethane, toluene, xylene, or combinations thereof.
In another preferred embodiment, the molar ratio of the compound of formula II to the compound of formula III is from 0.5 to 2: 0.5 to 2; preferably about 1: 1.
in another preferred embodiment, the reaction time is 1 to 15 hours, preferably 2 to 10 hours, more preferably 0.5 to 5 hours.
In another preferred embodiment, the reaction is carried out under an organic base catalyst.
In another preferred embodiment, the organic base catalyst is selected from the group consisting of: dimethylaminopyridine (DMAP), Diisopropylethylamine (DIPEA), or a combination thereof.
In another preferred embodiment, the reaction is carried out under acid catalysis.
In another preferred embodiment, the acid catalyst is an acid scavenger.
In another preferred embodiment, the acid scavenger is selected from the group consisting of: triethylamine, pyridine, diethylamine, piperidine, or combinations thereof.
In another preferred example, the method further comprises the step (1-1): dissolving a compound shown in a formula II, an organic base and an acid-binding agent in an inert solvent at the temperature of-50-0 ℃, and dropwise adding a compound shown in a formula III for reaction.
In another preferred example, the steps further include step (1-2): and (2) heating the mixture obtained in the step (1-1) to room temperature for reaction.
In another preferred example, the steps further include the step (1-3): the reaction was quenched with water.
In a third aspect of the invention, there is provided a process for the preparation of a compound of formula I-c, said process comprising the steps of:
in an inert solvent, the compound of the formula I-b is subjected to a ring-opening reaction to prepare the compound of the formula I-c, wherein R1' is as definedAs described above.
In another preferred embodiment, the inert solvent is selected from the group consisting of: methanol, ethanol, tetrahydrofuran, or combinations thereof.
In another preferred embodiment, the reaction is carried out under alkaline conditions.
In another preferred embodiment, the base is selected from the group consisting of: potassium carbonate, sodium bicarbonate, potassium bicarbonate, or a combination thereof.
In a fourth aspect of the invention, there is provided a pharmaceutical composition comprising a therapeutically effective amount of one or more selected from the compounds according to the first aspect of the invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
In a fifth aspect of the invention, there is provided the use of a compound according to the first aspect of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to the fourth aspect of the invention, in the manufacture of a medicament for the prevention and treatment of diseases associated with JAK kinases and JAK kinase inhibitors.
In another preferred embodiment, the JAK kinase is selected from the group consisting of JAK1, JAK2 and JAK3 kinases.
In another preferred embodiment, the disease is an autoimmune and chronic inflammatory disease.
In another preferred embodiment, the disease is selected from the group consisting of: systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, type II diabetes, inflammatory bowel disease, biliary cirrhosis, uveitis, Crohn's disease, ulcerative colitis, bullous pemphigoid, sarcoidosis, psoriasis, psoriatic arthritis, autoimmune myositis, Wegener's granulomatosis, Graves ' ophthalmopathy, allergic dermatitis, and asthma.
In a sixth aspect, the present invention provides a method for non-therapeutically inhibiting JAK kinase activity, comprising the steps of: contacting a compound according to the first aspect of the invention, or a pharmaceutically acceptable salt thereof, with a JAK kinase, thereby inhibiting the JAK kinase.
In a seventh aspect, the present invention provides a method for inhibiting JAK kinase activity or treating a JAK kinase-associated disease, comprising the steps of: contacting a compound according to the first aspect of the invention, or a pharmaceutically acceptable salt thereof, with a JAK kinase, thereby inhibiting the JAK kinase.
In another preferred embodiment, the method comprises administering to a mammal in need thereof a therapeutically effective amount of a compound according to the first aspect of the invention or a pharmaceutically acceptable salt thereof, or administering a therapeutically effective amount of a pharmaceutical composition according to the fourth aspect of the invention.
It is to be understood that within the scope of the present invention, the above-described features of the present invention and those specifically described below (e.g., in the examples) may be combined with each other to form new or preferred embodiments. Not to be reiterated herein, but to the extent of space.
Detailed Description
The inventor of the invention has long and intensive research, and unexpectedly finds that a compound shown as a formula I or a pharmaceutically acceptable salt thereof has an immunosuppressive effect and can be used for treating immune-related diseases for the first time. The present invention has been completed based on this finding.
Description of the terms
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.
As used herein, the term "about" when used in reference to a specifically recited value means that the value may vary by no more than 1% from the recited value. For example, as used herein, the expression "about 100" includes 99 and 101 and all values in between (e.g., 99.1, 99.2, 99.3, 99.4, etc.).
As used herein, the term "comprising" or "includes" can be open, semi-closed, and closed. In other words, the term also includes "consisting essentially of …," or "consisting of ….
As used herein, the term "substituted" refers to one or more hydrogen atoms on a group being substituted with a substituent selected from the group consisting of: halogen, amino, nitro, C1-C4 alkyl.
In this application, the term "alkyl" as a group or as part of another group (e.g., as used in halo-substituted alkyl and the like groups) refers to a fully saturated straight or branched hydrocarbon chain radical consisting only of carbon and hydrogen atoms, having, for example, 1 to 12 (preferably 1 to 8, more preferably 1 to 6) carbon atoms, and attached to the remainder of the molecule by a single bond, including, for example, but not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-methylbutyl, 2-dimethylpropyl, n-hexyl, heptyl, 2-methylhexyl, 3-methylhexyl, octyl, nonyl, decyl and the like. The term "C3-C10 alkyl" refers to a straight or branched chain alkyl group having 3 to 10 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or the like.
In the present application, the term "alkenyl" as a group or part of another group means a straight or branched hydrocarbon chain group consisting of only carbon atoms and hydrogen atoms, containing at least one double bond, having, for example, 2 to 14 (preferably 2 to 10, more preferably 2 to 6) carbon atoms, and being connected to the rest of the molecule by a single bond, such as, but not limited to, vinyl, propenyl, allyl, but-1-enyl, but-2-enyl, pent-1, 4-dienyl, and the like.
In the present application, the term "alkynyl" as a group or part of another group refers to a straight or branched hydrocarbon chain group consisting solely of carbon and hydrogen atoms, containing at least one triple bond, optionally containing at least one double bond, having for example 2 to 14 (preferably 2 to 10, more preferably 2 to 6) carbon atoms and being connected to the rest of the molecule by single bonds, such as but not limited to ethynyl, prop-1-ynyl, but-1-ynyl, pent-1-en-4-ynyl and the like.
In this application, the term "heterocyclyl" as a group or part of another group means a stable 3-to 20-membered non-aromatic cyclic group consisting of 2 to 14 carbon atoms and 1 to 6 heteroatoms selected from nitrogen, phosphorus, oxygen, and sulfur. Unless otherwise specifically indicated in the specification, a heterocyclic group may be a monocyclic, bicyclic, tricyclic or higher ring system, which may include fused ring systems, bridged ring systems or spiro ring systems; wherein the nitrogen, carbon or sulfur atom in the heterocyclic group may be optionally oxidized; the nitrogen atoms may optionally be quaternized; and the heterocyclic group may be partially or fully saturated. The heterocyclic group may be attached to the rest of the molecule via a carbon atom or a heteroatom and by a single bond. In heterocyclic groups containing fused rings, one or more of the rings may be aryl or heteroaryl as defined below, provided that the point of attachment to the rest of the molecule is a non-aromatic ring atom. For the purposes of the present invention, heterocyclyl is preferably a stable 4-to 11-membered non-aromatic monocyclic, bicyclic, bridged or spiro group containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, more preferably a stable 4-to 8-membered non-aromatic monocyclic, bicyclic, bridged or spiro group containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur. Examples of heterocyclyl groups include, but are not limited to: pyrrolidinyl, morpholinyl, piperazinyl, homopiperazinyl, piperidinyl, thiomorpholinyl, 2, 7-diaza-spiro [3.5] nonan-7-yl, 2-oxa-6-aza-spiro [3.3] heptan-6-yl, 2, 5-diaza-bicyclo [2.2.1] heptan-2-yl, azetidinyl, pyranyl, tetrahydropyranyl, thiopyranyl, tetrahydrofuranyl, oxazinyl, dioxolanyl, tetrahydroisoquinolinyl, decahydroisoquinolinyl, imidazolinyl, imidazolidinyl, quinolizinyl, thiazolidinyl, isothiazolidinyl, isoxazolidinyl, indolinyl, octahydroindolyl, octahydroisoindolyl, pyrrolidinyl, pyrazolidinyl, phthalimidyl, and the like.
In this application, the term "aryl" as a group or as part of another group means a conjugated hydrocarbon ring system group having 6 to 18 carbon atoms, preferably having 6 to 10 carbon atoms. For the purposes of the present invention, an aryl group may be a monocyclic, bicyclic, tricyclic or higher polycyclic ring system and may also be fused to a cycloalkyl or heterocyclic group as defined above, provided that the aryl group is attached to the remainder of the molecule by a single bond via an atom on the aromatic ring. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, phenanthrenyl, fluorenyl, 2, 3-dihydro-1H-isoindolyl, 2-benzoxazolinone, 2H-1, 4-benzoxazin-3 (4H) -one-7-yl, and the like. The term "C6-C10 aryl" refers to aryl groups having 6-10 carbon atoms, including monocyclic or bicyclic aryl groups, such as phenyl, naphthyl, or the like.
In this application, the term "heteroaryl" as a group or part of another group means a 5-to 16-membered conjugated ring system group having 1 to 15 carbon atoms (preferably having 1 to 10 carbon atoms) and 1 to 6 heteroatoms selected from nitrogen, oxygen and sulfur in the ring. Unless otherwise specifically indicated in the specification, a heteroaryl group may be a monocyclic, bicyclic, tricyclic or higher ring system, and may also be fused to a cycloalkyl or heterocyclic group as defined above, provided that the heteroaryl group is attached to the rest of the molecule by a single bond via an atom on the aromatic ring. The nitrogen, carbon or sulfur atoms in the heteroaryl group may be optionally oxidized; the nitrogen atoms may optionally be quaternized. For the purposes of the present invention, heteroaryl is preferably a stable 5-to 12-membered aromatic group containing 1 to 5 heteroatoms selected from nitrogen, oxygen and sulfur, more preferably a stable 5-to 10-membered aromatic group containing 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur or a 5-to 6-membered aromatic group containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur. Examples of heteroaryl groups include, but are not limited to, thienyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, oxadiazolyl, isoxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzimidazolyl, benzopyrazolyl, indolyl, furyl, pyrrolyl, triazolyl, tetrazolyl, triazinyl, indolizinyl, isoindolyl, indazolyl, isoindolyl, purinyl, quinolyl, isoquinolyl, diazonaphthyl, naphthyridinyl, quinoxalinyl, pteridinyl, carbazolyl, carbolinyl, phenanthridinyl, phenanthrolinyl, acridinyl, phenazinyl, isothiazolyl, benzothiazolyl, benzothienyl, oxazolyl, cinnolinyl, quinazolinyl, thiophenyl, indolizinyl, orthophenanthrolidinyl, isoxazolyl, phenoxazinyl, phenothiazinyl, 4,5,6, 7-tetrahydrobenzo [ b ] thienyl, naphthopyridyl, pyridinyl, and the like, [1,2,4] triazolo [4,3-b ] pyridazine, [1,2,4] triazolo [4,3-a ] pyrazine, [1,2,4] triazolo [4,3-c ] pyrimidine, [1,2,4] triazolo [4,3-a ] pyridine, imidazo [1,2-b ] pyridazine, imidazo [1,2-a ] pyrazine and the like. The term "C1-C10 heteroaryl" refers to a heteroaryl group having 1-10 carbon atoms, such as pyrrolyl, pyridyl, furyl, oxazolyl, or the like.
The term "halogen" refers to F, Cl, Br and I.
Certain chemical groups defined herein are preceded by a shorthand notation to indicate the total number of carbon atoms present in the group. For example, C1-C6 alkyl refers to an alkyl group as defined below having a total of 1 to 6 carbon atoms. The total number of carbon atoms in the shorthand notation excludes carbons that may be present in a substituent of the group.
In the present application, the term "pharmaceutically acceptable salts" includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.
"pharmaceutically acceptable acid addition salts" refers to salts with inorganic or organic acids which retain the biological effectiveness of the free base without other side effects. Inorganic acid salts include, but are not limited to, hydrochloride, hydrobromide, sulfate, nitrate, phosphate, and the like; organic acid salts include, but are not limited to, formates, acetates, 2-dichloroacetates, trifluoroacetates, propionates, caproates, caprylates, caprates, undecylenates, glycolates, gluconates, lactates, sebacates, adipates, glutarates, malonates, oxalates, maleates, succinates, fumarates, tartrates, citrates, palmitates, stearates, oleates, cinnamates, laurates, malates, glutamates, pyroglutamates, aspartates, benzoates, methanesulfonates, benzenesulfonates, p-toluenesulfonates, alginates, ascorbates, salicylates, 4-aminosalicylates, napadisylates, and the like. These salts can be prepared by methods known in the art.
"pharmaceutically acceptable base addition salts" refers to salts with inorganic or organic bases which maintain the biological effectiveness of the free acid without other side effects. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like. Preferred inorganic salts are ammonium, sodium, potassium, calcium and magnesium salts. Salts derived from organic bases include, but are not limited to, the following: primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, triethanolamine, dimethylethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine, polyamine resins, and the like. Preferred organic bases include isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine. These salts can be prepared by methods known in the art.
Pharmaceutical composition and mode of administration
In the present application, a "pharmaceutical composition" refers to a formulation of a compound of the present invention with a vehicle generally accepted in the art for delivery of biologically active compounds to a mammal (e.g., a human). The medium includes a pharmaceutically acceptable carrier. The purpose of the pharmaceutical composition is to facilitate administration to an organism, facilitate absorption of active ingredients and exert biological activity.
The term "pharmaceutically acceptable" as used herein refers to a substance (e.g., carrier or diluent) that does not affect the biological activity or properties of the compounds of the present invention and is relatively non-toxic, i.e., the substance can be administered to an individual without causing an adverse biological response or interacting in an adverse manner with any of the components contained in the composition.
As used herein, "pharmaceutically acceptable excipient" includes, but is not limited to, any adjuvant, carrier, excipient, glidant, sweetener, diluent, preservative, dye/colorant, flavoring agent, surfactant, wetting agent, dispersing agent, suspending agent, stabilizing agent, isotonic agent, solvent, or emulsifying agent that is approved by the relevant governmental regulatory agency for human or livestock use.
In the present invention, the term "effective amount" refers to an amount of a therapeutic agent that treats, alleviates, or prevents a target disease or condition, or an amount that exhibits a detectable therapeutic or prophylactic effect. The precise effective amount for a subject will depend upon the size and health of the subject, the nature and extent of the disorder, and the therapeutic agent and/or combination of therapeutic agents selected for administration. Therefore, it is not useful to specify an exact effective amount in advance. However, for a given condition, the effective amount can be determined by routine experimentation and can be determined by a clinician.
A compound of formula I
According to the present invention, a compound of formula I, or a pharmaceutically acceptable salt thereof,
wherein the content of the first and second substances,
R1selected from the group consisting of: H. substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C4-C10 heterocyclyl, substituted or unsubstituted C1-C10 heteroaryl, -RaC(O)Rb、-R1’-NRcC(O)Rband-R1’-N＝CRcRb(ii) a And said substitution refers to having one or more substituents selected from the group consisting of group a 1: substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C4-C10 heterocyclyl, substituted or unsubstituted C1-C10 heteroaryl, halogen, -NH2-OH and-CN;
each Ra、RbEach independently selected from the group consisting of: hydrogen, -CN, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C3-C8 alkynyl, substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C4-C10 heterocyclyl, and substituted or unsubstituted C1-C10 heteroaryl, and said substitution refers to having one or more substituents selected from the following group a 2: halogen, amino, nitro, -OH, -CN, C1-C4 alkyl, and C1-C4 haloalkyl;
Rcis H or C1-C3 alkyl;
R1' is phenylOr cyclohexyl;
wherein the C4-C10 heterocyclyl and C1-C10 heteroaryl each independently have 1-3 heteroatoms selected from N, O and S.
Preparation of Compounds of formula I-b
The present invention also provides a process for the preparation of a representative compound I-b of the compound of formula I, said process comprising the steps of:
reacting a compound of formula II with a compound of formula III in an inert solvent to provide a compound of formula I-b, wherein R1' is as defined above.
In another preferred embodiment, the inert solvent is selected from the group consisting of: dichloromethane, trichloromethane, 1, 2-dichloroethane, toluene, xylene, or combinations thereof.
In another preferred embodiment, the molar ratio of the compound of formula II to the compound of formula III is from 0.5 to 2: 0.5 to 2; preferably about 1: 1.
in another preferred embodiment, the reaction time is 1 to 15 hours, preferably 2 to 10 hours, more preferably 0.5 to 5 hours.
In another preferred embodiment, the reaction is carried out under an organic base catalyst.
In another preferred embodiment, the organic base catalyst is selected from the group consisting of: dimethylaminopyridine (DMAP), Diisopropylethylamine (DIPEA), or a combination thereof.
In another preferred embodiment, the reaction is carried out under acid catalysis.
In another preferred embodiment, the acid catalyst is an acid scavenger.
In another preferred embodiment, the acid scavenger is selected from the group consisting of: triethylamine, pyridine, diethylamine, piperidine, or combinations thereof.
In another preferred example, the method further comprises the step (1-1): dissolving a compound shown in a formula II, an organic base and an acid-binding agent in an inert solvent at the temperature of-50-0 ℃, and dropwise adding a compound shown in a formula III for reaction.
In another preferred example, the steps further include step (1-2): and (2) heating the mixture obtained in the step (1-1) to room temperature for reaction.
In another preferred example, the steps further include the step (1-3): the reaction was quenched with water.
Preparation of Compounds of formula I-c
The present invention also provides a process for the preparation of a representative compound I-c of the compound of formula I, said process comprising the steps of:
in an inert solvent, the compound of the formula I-b is subjected to a ring-opening reaction to prepare the compound of the formula I-c, wherein R1' is as defined above.
In another preferred embodiment, the inert solvent is selected from the group consisting of: methanol, ethanol, tetrahydrofuran, or combinations thereof.
In another preferred embodiment, the reaction is carried out under alkaline conditions.
In another preferred embodiment, the base is selected from the group consisting of: potassium carbonate, sodium bicarbonate, potassium bicarbonate, or a combination thereof.
Use of
The compounds of formula I and related structures of the present invention are useful for the treatment and/or prevention of diseases including, but not limited to: autoimmune and chronic inflammatory diseases, such as systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, type II diabetes, inflammatory bowel disease, biliary cirrhosis, uveitis and other disorders, such as crohn's disease, ulcerative colitis, bullous pemphigoid, sarcoidosis, psoriasis, psoriatic arthritis, autoimmune myositis, wegener's granulomatosis, graves ' ophthalmopathy, allergic dermatitis and asthma.
The main advantages of the invention are:
1. provides a compound shown as a formula I.
2. Provides a specific immune response inhibitor with novel structure, a preparation method and application thereof.
3. Pharmaceutical compositions for treating diseases associated with JAK kinases are provided.
The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. The experimental procedures, in which specific conditions are not noted in the following examples, are generally carried out under conventional conditions or conditions recommended by the manufacturers. Unless otherwise indicated, percentages and parts are percentages and parts by weight.
The test materials and reagents used in the following examples are commercially available without specific reference.
Example 1 preparation of compound 1: N-methyl-N- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) phenyl-1, 4-diamine
A solution of 1.53g of 4-chloropyrrolopyrimidine, 4.6g N-methyl-p-nitroaniline, 4M HCl in dioxane was weighed out and heated to 130 ℃ overnight in 40mL dioxane. The mixture was cooled to room temperature and concentrated to dryness under reduced pressure. The residue was slurried with ethyl acetate until most of the N-methyl-p-nitroaniline disappeared, the resulting solid was dissolved in a mixture of methanol and triethylamine (1.5eq), silica gel was added, and concentrated to dryness under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with a dichloromethane/methanol 30/1 system to give 1.4g N-methyl-N- (4-nitrophenyl) -7H-pyrrolo [2,3-d ] pyrimidin-4-amine in 91.5% yield.
Stirring 11g of the product and 10% Pd/C in a methanol closed system with a hydrogen balloon until the raw materials completely react, filtering the system, concentrating the filtrate under reduced pressure to dryness, and pulping the residue with methanol to obtain 8g of a compound with the yield of 72.7%.
The structures of compound 2 and compound 3 are shown in formula I-b below:
| examples | Structural formula (I) | R1’ |
| 2 | Formula I-b | Phenyl radical |
| 3 | Formula I-b | Cyclohexyl radical |
Example 2 preparation of compound 2: 5-methyl-isoxazole- { 4-methyl- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) -amino ] -phenyl } -4-amide
100mg of N-methyl-N- (7H-pyrrolo [2, 3-d) was weighed out separately]Pyrimidine-4-) phenyl-1, 4-diamine and 16mg DMAP are put into a three-neck flask, 20mL dichloromethane is added and stirred to be dissolved, the temperature is cooled to about minus 20 ℃, and 100mg triethylamine is dripped into the reaction solution. Then, 103mg of 5-methylisoxazole-4-carbonyl chloride is slowly added dropwise into a 5mL dichloromethane solution, after the dropwise addition, the solution is naturally and slowly raised to room temperature for reaction for 5 hours, and the reaction is monitored by TLC until the reaction is finished. Adding 20mL of water to quench the reaction, separating the solution, extracting, washing the aqueous phase with dichloromethane for 3 times, combining the organic phases, and adding anhydrous Na2SO4Drying, separating with silica gel column chromatography, and eluting with ethyl acetate/n-hexane 1/1 system to obtain 72mg of product with yield of 72%.
Example 3 preparation of compound 3: 5-methyl-isoxazolo- { 4-methyl- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) -amino ] -cyclohexyl } -amine
Respectively weighing100mg of N-methyl-N- (7H-pyrrolo [2, 3-d)]Pyrimidine-4-) benzene-1, 4-diamine and 16mg DMAP are put into a three-neck flask, 20mL dichloromethane is added and stirred to be dissolved, the temperature is cooled to about minus 20 ℃, and 100mg triethylamine is dripped into the reaction solution. Then, 103mg of 5-methylisoxazole-4-carbonyl chloride is slowly added dropwise into a 5mL dichloromethane solution, after the dropwise addition, the solution is naturally and slowly raised to room temperature for reaction for 5 hours, and the reaction is monitored by TLC until the reaction is finished. Adding 20mL of water to quench the reaction, separating the solution, extracting, washing the aqueous phase with dichloromethane for 3 times, combining the organic phases, and adding anhydrous Na2SO4Drying, separating with silica gel column chromatography, and eluting with ethyl acetate/n-hexane 1/1 system to obtain 64mg product with yield of 64%.
The structures of compound 4 and compound 5 are shown below in formulas I-c:
| examples | Structural formula (I) | R1’ |
| 4 | Formula I-c | Phenyl radical |
| 5 | Formula I-c | Cyclohexyl radical |
Example 4 preparation of compound 4: 2-cyano-3-hydroxy-2-butene- {4- [ methyl- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) -amino ] -phenyl ] -amide
Weighing 100mg of compound 2 in a three-neck flask, adding 30mL of methanol, stirring and dissolving, cooling to 0 ℃, slowly dropwise adding 1mL of saturated sodium bicarbonate aqueous solution, after dropwise adding, continuously stirring and reacting for 4 hours at the temperature, and tracking and reacting by TLC until the reaction is finished. Distilling off methanol under reduced pressure, adding 20mL of water, separating, extracting, washing the water phase with dichloromethane for 3 times, combining the organic phases, and adding anhydrous Na2SO4Drying and separation by silica gel column chromatography eluting with a dichloromethane/methanol 20/1 system gave 47mg of product in 47% yield.
Example 5 preparation of compound 5: 2-cyano-3-hydroxy-2-butene- {4- [ methyl- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) -amino ] -cyclohexyl ] -amide
Weighing 100mg of compound 3 in a three-neck flask, adding 30mL of methanol, stirring and dissolving, cooling to 0 ℃, slowly dropwise adding 1mL of saturated sodium bicarbonate aqueous solution, after dropwise adding, continuously stirring and reacting for 4h at the temperature, and tracking and reacting by TLC until the reaction is finished. Distilling off methanol under reduced pressure, adding 20mL of water, separating, extracting, washing the water phase with dichloromethane for 3 times, combining the organic phases, and adding anhydrous Na2SO4Drying and elution with a dichloromethane/methanol 20/1 system gave 52mg of product in 52% yield.
Example 6 preparation of compound 6: 3-hydroxy-2- (1- {4- [ methyl- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) -amino ] -iminophenyl } -ethyl) -2-butenenitrile
1g of compound 5, 1g of 1- (5-methyl-4-isoxazole) -1-ethanone and 25mL of DMF are weighed and heated at 150 ℃ for 5 h. 75mL of water is added dropwise, the mixture is stirred for 1h, filtered, and a filter cake is dissolved in a dichloromethane/methanol system and Na2SO4Drying, separating by silica gel column chromatography, and separating by dichloromethane/methanol (60: 1, 0.9g of product is obtained, yield: 90 percent.
EXAMPLE 7 Selective inhibition of JAK1-3 enzymatic Activity by Compounds of the invention
Test compounds were dissolved in DMSO to make 10mM stock. Before use, compounds were diluted to 1mM in DMSO and 3-fold stepwise diluted to 11 concentrations, and after buffer preparation, JAK1, JAK2, and JAK3 were mixed with substrate and compounds of different concentrations diluted in advance, and left at room temperature for 30 minutes, each concentration being double-well. Adding ATP, reacting at room temperature for 90 minutes, adding the antibody after the reaction is finished, and incubating at room temperature for 60 minutes, and then acquiring data by Envision detection, wherein the data are shown in table 1.
TABLE 1 Compound JAK enzyme selectivity
EXAMPLE 8 inhibitory Activity of Compounds of the present invention on the proliferation of mouse splenocytes induced by antibodies to the mitogens ConA and CD3/CD28
The CD3 and CD28 monoclonal antibodies can specifically bind to CD3 and CD28 on the surface of T cells, cause the cross-linking of T cell TCR-CD3 complexes, and induce the activated proliferation of T cells without the assistance of a second signal. This process is similar to antigen-induced T cell activation.
Inhibition of mouse splenocyte proliferation induced by CD3/CD28 antibody: add 100uL of cell suspension per well, i.e. 5 x 105Per well, plus or without 50uL ConA at 2.5ug/uL and 50uL of different concentrations of inhibitor, negative control wells were filled with 50uL of complete 1640 medium. Culturing for 48 hours, collecting 100 uL/well of cell culture supernatant for subsequent ELISA detection, adding 10 uL/well of CCK8 reagent, and detecting the cell proliferation. The proliferation of the immune cells in each group was observed under a microscope.
Experiment for inhibition of mitogen ConA-induced splenocyte proliferation in mice: aseptically prepared C57BL/6 mouse splenocytes, adjusted to a cell concentration of 5 x 10 in complete 1640 medium6Per mL, 100uL of cell suspension, 5X 10, was added to each well of a 5ug/mL CD3 pre-plated plate5Add CD28 at a concentration of 8ug/mL and different concentrations of 50uL inhibitor (Compounds 1-6) to/well with or without 50uL, and complement 50uL of complete 1640 medium in negative control wells. After culturing for 144 hours, collecting 100 uL/well of cell culture supernatant for subsequent ELISA detection, and adding 10 uL/well of CCK8 reagent to detect the cell proliferation. Microscopic observationThe proliferation of immune cells in each group was examined and the EC50 value was calculated.
The results of the inhibitory ability of each compound against mouse splenocyte proliferation induced by the antibodies to mitogen ConA and CD3/CD28 are shown in Table 2:
TABLE 2 inhibitory Activity of the Compounds of the present invention against mouse splenocyte proliferation induced by antibodies to the mitogen ConA and CD3/CD28 EC50
| Compound numbering | ConA Induction (μ M) | CD3/CD28(μM) |
| 1 | 53.88 | 22.73 |
| 2 | 40.34 | 15.09 |
| 3 | 90.71 | 65.67 |
| 4 | 61.22 | 30.85 |
| 5 | >200 | >100 |
| 6 | 93.34 | 52.79 |
| Control Compound (A771726) | >200 | >200 |
With ConA as a stimulus, the compounds 1,2 and 3 begin to have inhibitory effects on lymphocyte proliferation at a concentration of 10uM, and the inhibitory effects become more apparent as the concentration increases. Whereas compound 4 showed some inhibition only at 100 and 200uM concentrations.
The compound 1 and the compound 3 start to have the inhibition effect on the proliferation of lymphocytes at the concentration of 10uM by taking anti-CD 3/CD28 as a stimulus, and the inhibition effect is obviously increased along with the increase of the concentration; the compound 2 starts to have the inhibition effect on the lymphocyte proliferation at the concentration of 50uM, but the inhibition effect is sharply increased along with the increase of the concentration; although compound 4 also initially exhibited inhibitory effects on lymphocyte proliferation at 50uM, the inhibitory effects increased slowly with increasing concentration, suggesting that it is more advantageous to maintain the isoxazole ring and the phenyl group at the R1 position.
The experimental result shows that the compounds 1 and 3 mainly inhibit specific immunity and have weak non-specific immunity induced by mitogen. For most autoimmune diseases, specific immune (humoral immunity and cellular immunity) disorders play an important role in the development of the disease, inhibit specific immune responses, correct specific immune disorders, and block the progression and exacerbation of the disease.
All documents referred to herein are incorporated by reference into this application as if each were individually incorporated by reference. Furthermore, it should be understood that various changes and modifications of the present invention can be made by those skilled in the art after reading the above teachings of the present invention, and these equivalents also fall within the scope of the present invention as defined by the appended claims.
Claims (15)
1. A compound of formula I or a pharmaceutically acceptable salt thereof,
wherein the content of the first and second substances,
R1selected from the group consisting of: -R1’-NRcC(O)Rband-R1’-N＝CRcRb；
RbSelected from the group consisting of: substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C6 aryl, and substituted or unsubstituted heteroaryl, and said substitution refers to having one or more substituents selected from the group consisting of group a 2: halogen, -OH, -CN, C1-C4 alkyl, and C1-C4 haloalkyl;
Rcis H or C1-C3 alkyl;
R1' is phenyl or cyclohexyl;
wherein said heteroaryl refers to a 5-to 6-membered aromatic group having 1-3 heteroatoms selected from N, O and S.
2. The compound of formula I, or a pharmaceutically acceptable salt thereof, according to claim 1, wherein R isbIs a substituted or unsubstituted C2-C8 alkenyl group, or a substituted or unsubstituted isoxazolyl group, and the substitution refers to having one or more substituents selected from the following group a 2: halogen, -OH, -CN, C1-C4 alkyl.
3. The compound of formula I according to claim 1, or a pharmaceutically acceptable salt thereof, selected from compounds of formula I-b or I-c as follows:
in the formulae, R1' is as defined in claim 1.
4. The compound of formula I, or a pharmaceutically acceptable salt thereof, according to claim 1, selected from the group consisting of:
5-methyl-isoxazole- { 4-methyl- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) -amino ] -phenyl } -4-amide;
5-methyl-isoxazole- { 4-methyl- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) -amino ] -cyclohexyl } -amine;
2-cyano-3-hydroxy-2-butene- {4- [ methyl- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) -amino ] -phenyl ] -amide;
2-cyano-3-hydroxy-2-butene- {4- [ methyl- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) -amino ] -cyclohexyl ] -amide; and
3-hydroxy-2- (1- {4- [ methyl- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) -amino ] -iminophenyl } -ethyl) -2-butenenitrile.
5. A process for preparing a compound of formula I-b, comprising the steps of:
reacting a compound of formula II with a compound of formula III in an inert solvent to provide a compound of formula I-b, wherein R1' is as defined in claim 1.
6. The method of claim 5, wherein the molar ratio of the compound of formula II to the compound of formula III is from 0.5 to 2: 0.5-2.
7. The method of claim 5, wherein the molar ratio of the compound of formula II to the compound of formula III is 1: 1.
8. a process for preparing a compound of formula I-c, comprising the steps of;
in an inert solvent, the compound of the formula I-b is subjected to a ring-opening reaction to prepare the compound of the formula I-c, wherein R1' is as defined in claim 1.
9. A pharmaceutical composition comprising a therapeutically effective amount of one or more selected from the compounds of claim 1, or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable excipient.
10. Use of a compound of claim 1, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 9, in the manufacture of a medicament for the prevention and treatment of diseases associated with JAK kinases and JAK kinase inhibitors.
11. The use of claim 10, wherein the JAK kinase is selected from the group consisting of JAK1, JAK2 and JAK3 kinases.
12. The use according to claim 10, wherein the disease is an autoimmune and chronic inflammatory disease.
13. The use according to claim 10, wherein the disease is selected from the group consisting of: systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, type II diabetes, inflammatory bowel disease, biliary cirrhosis, uveitis, bullous pemphigoid, sarcoidosis, psoriasis, psoriatic arthritis, autoimmune myositis, Wegener's granulomatosis, Graves ophthalmopathy, allergic dermatitis, and asthma.
14. The use of claim 13, wherein the inflammatory bowel disease is selected from the group consisting of: crohn's disease and ulcerative colitis.
15. A method for non-therapeutically inhibiting JAK kinase activity in vitro comprising the steps of: contacting a compound of claim 1, or a pharmaceutically acceptable salt thereof, with a JAK kinase, thereby inhibiting the JAK kinase.
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| CN201610100165.5A CN107098908B (en) | 2016-02-23 | 2016-02-23 | Preparation method and application of pyrrolopyrimidine compound |
| PCT/CN2017/074446 WO2017143990A1 (en) | 2016-02-23 | 2017-02-22 | Method for preparing pyrrolopyrimidine compound and application thereof |
| US16/092,394 US11591333B2 (en) | 2016-02-23 | 2017-02-22 | Substituted pyrrolo[2,3-d]pyrimidines as janus kinase inhibitors |
| EP17755819.4A EP3421473B1 (en) | 2016-02-23 | 2017-02-22 | Method for preparing pyrrolopyrimidine compounds and application thereof |
| HK19100586.9A HK1258226A1 (en) | 2016-02-23 | 2019-01-14 | Method for preparing pyrrolopyrimidine compound and application thereof |
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| US3037980A (en) * | 1955-08-18 | 1962-06-05 | Burroughs Wellcome Co | Pyrrolopyrimidine vasodilators and method of making them |
| PA8474101A1 (en) * | 1998-06-19 | 2000-09-29 | Pfizer Prod Inc | PYROLEUM [2,3-D] PIRIMIDINE COMPOUNDS |
| CZ20004727A3 (en) * | 1998-06-19 | 2002-03-13 | Pfizer Products Inc. | Derivatives of pyrrolo[2,3-d]pyrimidine |
| ATE423120T1 (en) * | 2000-06-26 | 2009-03-15 | Pfizer Prod Inc | PYRROLOÄ2,3-DÜPYRIMIDINE COMPOUNDS AS IMMUNOSUPPRESSIVE ACTIVES |
| AP2012006192A0 (en) * | 2009-10-15 | 2012-04-30 | Pfizer | PyrroloÄ2,3-DÜ pyrimidine compounds. |
| ES2461967T3 (en) * | 2009-12-18 | 2014-05-21 | Pfizer Inc. | Pyrrolo [2,3-d] pyrimidine compounds |
| CA2836417A1 (en) * | 2011-05-17 | 2012-11-22 | Principia Biopharma Inc. | Azaindole derivatives as tyrosine kinase inhibitors |
| US9527851B2 (en) * | 2011-12-21 | 2016-12-27 | Jiangsu Hengrui Medicine Co., Ltd. | Pyrrole six-membered heteroaryl ring derivative, preparation method thereof, and medicinal uses thereof |
| PT2874630T (en) * | 2012-07-20 | 2019-01-31 | Zoetis Services Llc | Dosing regimen for janus kinase (jak) inhibitors |
| CN103896946B (en) * | 2012-12-28 | 2018-04-03 | 浙江导明医药科技有限公司 | For preventing and treating the noval chemical compound of various autoimmune disease |
| CN105732636B (en) * | 2014-12-30 | 2020-04-21 | 广东东阳光药业有限公司 | Heteroaromatic compounds and their use in medicine |
| KR101771219B1 (en) * | 2015-08-21 | 2017-09-05 | 양지화학 주식회사 | Janus kinase 1 selective inhibitors and their pharmaceutical use |
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